2 PLAY A CENTRAL REGULATORY AND EFFECTOR ROLE IN THE IMMUNE SYSTEM T CELLS:PLAY A CENTRAL REGULATORYAND EFFECTOR ROLE IN THE IMMUNE SYSTEMRegulation:is mediated by cytokines and cell-to-cell contactB cells and immunoglobulin productionT cell cytotoxicitynatural killer cells (NK)cell chemotaxis Effector function:T cell mediated specific cytotoxicity
3 DIFFERENTIATION OF T CELLS plays in thymuscell-to-cell contact with epithelialand dendritic cellshumoral factors thymic hormones:small peptidesthymosine, thymopoetinimmunomodulation
4 THE MOST IMPORTANT EVENTS IN INTRATHYMIC DEVELOPMENT OF T CELLS T cells in thymus:proliferate and differentiate(functional cell-surface molecules)rearrange genetic information coding TcRexpress TcR heterodimers on the surfaceinduction of self tolerance is generated
5 DIFFERENTIATION OF T CELLS migration in to thymus is non-random (homing) humoral chemotactic factors (chemokines) specific surface interactionsdifferentiation is characterized by: migration from subcapsular sinus into medulla proliferation morfological changes changes in surface moleculesmajority of thymocytes is dying by apoptosisdue to differentiation failure
6 MEMBRANE MOLECULES OF T CELLS receptors for antigen: heterodimers TcR, TcRpan T cells: expressed on all T cells (CD7, CD2, CD3)subpopulations: helper inducer T cells CD4+suppressor cytotoxic T cells CD8+other subsets: thymocytes (CD1)
7 FUNCTION OF SURFACE MOLECULES: recognition (TcR)activation signals transmission (CD3)activation (HLA DR, IL-2R)accessory (CD4, CD8)costimulatory (CD28, CTLA-4)adhesion (CD2)
8 SURFACE MOLECULES OF T CELLS : recognition of AgTcRaccessorymoleculesCD4(CD8)CD3adhesionmoleculesCD2receptorsforcytokinesTcellICAM1CD69gbIL-2RCD28aCD25activationmoleculesbcostimulatorymoleculesaCTLA 4HLA II.
9 RECEPTORS FOR ANTIGEN ON T CELLS (TcR) are surface molecules responsible for specificrecognition of antigen which is processed in APCand presented in association with self HLA I (II) moleculesheterodimer, member of immunoglobulinefamily (domain)pre TcR is premature form of TcR found on thymocytesmajority of mature T cells express heterodimerminority of mature T cells express heterodimer
10 RECEPTORS FOR ANTIGEN ON T CELLS (TcR) variable TcR domain: unique amino acids compositionin antigen-combining site weak chemical forces between bindingsite of TcR and antigenic peptide are formed
11 RECEPTOR FOR ANTIGEN ON T CELLS (TcR) DNAVa (g)b (d)VSSDSSDJJSSCCSSSS
12 BASIC IMMUNOLOGICAL REPERTOIR OF TcR enormous number of T cells with different TcRs approx. 1x1016 different TcR specifities in theory overloading of theoretical coding capacity of genom genetic information for TcR is specifically organisedinto gene segments genetic information for TcR is specifically processed(gene rearrangement)
13 REARRANGEMENT OF TcR GENE SEGMENTS n = hundredsn = tensn = single3´C5´V1V2VnD1D2DnJ1Jn1223V3J17J2RAG -1,2J3V4VnV1V29D1D2rearrangementD3J1Jn3´C5´DNAV1D3J1J2JntranscriptionsplicingmRNANCtranslationVARIABILECONSTANTTcR chain
14 BASIC REPERTOIR OF TcR IS INCREASED BY uncorrected joining of V (D) gene segmentsto J genesrandom insertion of nucleotidesin to D-J region (enzyme TdT)unsuccesful rearrangement inducesapoptosis of thymocytes
15 EXPRESSION OF TcRTcR are expressed on cell in association with CD3 complex- TcR: small cytoplasmic part- CD3: trimolecular complex- noncovalently associated with TcR- transmission of activation signals in to cell- ITAM: Immunoreceptor Tyrosin-basedActivation Motifphosphorylation of tyrosine (kinases)- CD4: lck kinase- costimulatory interactions:- CD28, CTLA-4 B7.1, B7.2- critical level of activation signals is necessaryto start T cell activation and clonal expansion
16 TcR - CD 3 COMPLEX ON T CELLS abCD 3 COMPLEXSSVSSgdeSSSSSCSSSSSSSSSITAMITAMITAM: Immunoreceptor Tyrosin-based Activation Motif
17 IMMUNE RECOGNITION ACTIVATION OF T CELL clonal expansioneffector functionsanergyapoptosisno effect Krejsek, 2004
18 INTERACTIONS BETWEEN T CELL AND APC CELL adhesion interactionICAM-1clonalexpansionLFA-1accessory interactionendogenousantigenLFA-3CD2signal IIprocessing:peptide+ HLA IcostimulationCD28B7transcriptionfactorsCD4lcksignal IPRESENTATIONHLA IITcRabPSTATgCD3STATdeJAKPprocessing :peptide+ HLA IIcytokinesexogenousantigen
19 clonal expansion „context“ + = Ist signal = IInd signal activation of T CELLS RECOGNIZE ANTIGEN SPECIFICALLY IN „CONTEXT“COSTIMULATORY INTERACTIONS„context“(„danger patterns“)-accessory interactions- cytokine microenvironment= IInd signalCOGNITIVE INTERACTION:TcR, HLA-Ag, CD4 (CD8)= Ist signal+activation ofT cellsclonal expansionTcellsBcellsmigrationNKeffector and regulatory functions
20 INDUCTION OF SELF TOLERANCE Basic immunological repertoir of TcRs is generated: randomly in advance without presence of Ags in embryonal life in thymus Basic immunological repertoir of TcRs includes cloneswith high probability of self-recognition (autoreactive)of T cells.Autoreactive clones of T cells haveto be eliminated by selection.
21 SELECTION:POSITIVE SELECTION :T cell clones are tested for affinity (not recognition)of self HLA I, II moleculesNO AFFINITY: SELECTION (DELETION)NEGATIVE SELECTION :T cell clones are tested for recognition of self moleculesquantitative phenomenaEFFECTIVE RECOGNITION: SELECTION (DELETION)Mature T cell: toleration of selfrecognition of non-self.
22 REGULATORY AND EFFECTOR SUBSETS OF T CELLS mature T cells (TH0) differentiate into functionally distinctsubsets after antigen stimulationpresentationof microbial. Ag(LPS, CpG, lipoteichoic a.)dendritic c., macrophage,intensive, long termIL-12presentation ofenvironmental. Agnonmicrobial origin(allergens)B-cells,weak, short termIL-4TH0INHIBITIONINFIL-4TH1TH2TH1TH2TH1TH2cytotoxic reactivityantibodies production, isotypic switching
23 TH SUBSETS - CYTOKINES PRODUCED (T reg.)TNFINFTGF IL-2IL-10G-CSFIL-6IL-5IL-4
24 protective immunity against particular agent PHYSIOLOGICAL IMMUNE RESPONSE DURING INFECTIONIS REGULATED BY OPTIMAL BALANCE BETWEENTH1 AND TH2 SUBSETS.protective immunity against particular agentcould be either TH1 or TH2 driventhere are subsequent waves of both TH1 and TH2reactivities in the course of natural infectionsimplication for vaccine development
25 predominant TH pattern could be delineated for IMMUNOPATHOLOGY:predominant TH pattern could be delineated forparticular immunopathological diseases(TH1multiple sclerosis,TH2 atopy)the immunopathology –driven inflammation isregulated by the mix of both subsets activities
Your consent to our cookies if you continue to use this website.